16-methylene-progesterones and intermediates in the production thereof



United States Patent Office Patented Jan. 3, 1967 3 296 25616-METHYLENE-PROGESTERONES AND INTER- MEDIATES IN THE PRODUCTION THEREOFDavid Neville Kirk, Vladimir Petrow, Martin Stausfield,

and David Morton Williamson, London, England, assignors to The BritishDrug Houses Limited, London, England, a British company No Drawing.Filed July 24, 1959, Ser. No. 829,234 Claims priority, application GreatBritain, July 25, 1958, 24,077/58 12 Claims. (Cl. 260-23955) TOE: Me

(where R is hydrogen) for reasons hereinunder described- It is a furtherobject of the present invention to provide novel acyl esters prepared byacylation of the foregoing hydroxydione. These novel acyl esters,originally believed to be17a-acy1oxy-6a,16-dimethylpregn-4-ene-3,ZO-diones 4 are now believed tobe acyl esters having the formula Me O OMe i\ can H Me (II) where R isan acyl group containing up to carbon atoms employing as startingmaterial 3fi-hydr oXy-6,16-dimethylpregna-5,16-dien-20-one having theformula (I) OMe Me (III) The invention also provides the new compounds:60:,16 dimethyl 16,17 epoxy-pregn 4-ene-3,20-dione which is of value asan intermediate in the present invention, and

A new compound originally believed to be I7a-hYdIOXY-6a,16-dirnethylpregn-4-ene-3,20-dione, but now believed to bel7a-hydroxy-6a-methyl-l6methylenepregn-4-ene-3, ZO-dione (I; R=H), whichis of value as an intermediate particularly for conversion into acompound, originally believed to be17a-acetoxy-6u,l6-dimethylpregn-4-ene-3, 20-di0ne, but now believed tohave structure (H; R=Ac) which, together withits homologous esters, isof value as a progestational agent.

Thus, for example, in the standard Clauberg assay for the determinationof progestational activity it is found that the acetoxydione (II; R=Ac)is more than times as potent as dimethisterone(6a,2l-dimethylethisterone; 6a, 21-dimethylanhydrohydroxyprogesterone)on oral administration. As dimethisterone is known to be slightly morethan 10 times as active as anhydrohydroxyprogesterone (ethisterone) inthe Clauberg assay on oral administration it will be readily appreciatedby those skilled in the art that the acetoxydione (II; R=Ac) is aprogestational agent of quite unusual potency.

Other esters represented by Formula II (where R is an acyl groupcontaining up to 10 carbon atoms) likewise have progesterone-like orprogestational activity. The novel compounds represented by Formula H(where R is an acyl group as hereinabove defined) are useful in thetreatment of dysmenon'hea, amenorrhea, endometrosis and threatenedabortion in both clinical and veterinary practice.

The novel compounds of Formula H (where R is an acyl group ashereinabove defined) of this invention can be prepared and administeredto the animal organism in a wide variety of oral and subcutaneous dosageforms singly or in admixture with other coacting compounds. Thus theycan be associated with a pharmaceutical carrier which can be a solidmaterial or a liquid in which the compound is dissolved, dispersed orsuspended. The solid compositions can take the form of tablets, powders,capsules or pills preferably in unit dosage forms for simpleadministration or precise dosages. The liquid compositions can take theform of solutions, emulsions, suspensions, syrups or elixirs. Theacetoxydione (II; R=Ac) is the preferred acyl ester and is preferablyadministered orally in the form of tablets.

The invention employs as a starting material3B-hydroXy-6,l6-dimethylpregna-5,16-dien-20-one (HI) which material canbe prepared by condensing 6-methylpregnadienolone with diazomethane toyield the corresponding 35hydroxy-6-methyl-l6,17(2',3'-diaza-cyclopent-2'-eno) pregn-S-en-ZO-one,which on pyrolysis passes smoothly into the 6,16-dimethylpregnadienolone(IH) (above).

According to the present invention there is provided a process for thepreparation of 17oc-hYdIOXY-6a-methYl-l6-methylenepregn-4-ene-3,20-dione (I; R=H) which comprises oxidising 3/3hydroxy 6, 16-dimethylpregna-5 ,16- dien-ZO-one by the Oppenauerprocedure to give 6a,l6-dimethylpregnai,l6-diene-3,20-dione having theformula O OMe reacting the 6a,16-dimethylpregna-4,16-diene 3,20-dione 3with alkaline hydrogen peroxide to give a 16,17-epoxide having theformula treating the epoxide with a hydrogen halide and submitting theresultant product to reaction with Raney nickel in an organic solvent.

The resulting compound, originally believed to be 170:- hydroxy-6a,16dimethylpregn-4-ene-3,20-dione, but now believed to be17a-hydroxy-6a-methyl-16-methylenepregn- 4-ene-3,20-dione (I; R=H) maybe acylated to give an acyloxydione (II; where R has the same meaning asabove).

6a,l6-dimethylpregna 4,16 diene 3,20-dione is converted into thecorresponding 16,17-epxide by reaction with alkaline hydrogen peroxidein a water-miscible organic solvent, such for example as methanol orethanol, at temperatures between 0 C. and 100 C. and preferably at thereflux temperature of the reaction mixture.

The epoxy-derivative so obtained is then treated with a hydrogen halide.This transformation is preferably performed with hydrogen bromide in analiphatic acid, such as acetic acid, :mixed with an inert organicsolvent such as benzene or dioxan at a temperature which is preferablyin the region of 0 C. to 10 C. Alternatively, aqueous hydrogen iodidein-a water-miscible organic solvent, such as, for example, dioxan ortetrahydrofuran at temperatures in the region of 0 C. to 10 C. may beemployed.

The product so obtained is treated with Raney nickel in an organicsolvent such as ethanol or acetone at the ambient temperature to yieldthe 17a-hydroxy-6-methyl- 16-methy1enepregn-4-ene-3,20-dione (I; R=H).

Acetylation of the above 17a-hydroxy compound (I; R=H) to give theacetyl compound (II; R=Ac) is performed by methods well known to thoseskilled in the art. Thus acetylation, for example, may be performed 4 Wetherefore concluded that extension of this method to the 16-methylderivative (V) would analogously yield the corresponding 17ozhydroxy-6a,16 dimethylpregn-4-ene- 3,20-dione O OMe i l H (where R ishydrogen) which on enforced acylation would yield the corresponding17a-acyloxy-16-methyl derivative (IX; R=Acyl). The ultraviolet andinfra-red absorption spectra of our acylated product in fact proved tobe entirely consistent with the formulation (IX; R= Acetyl), i.e.

AEtOH max 239 m Indicates 3-ox0-A CHCI max 1,738 cm Indicates acetyl.01101; max 1,715- Indicates 20-00. 011013 max 1,6fi6 Indicates 3-CO.

01101 max 1,615- Indicates A employing an acetylation mixture comprisingglacial acetic acid, acetic anhydride and a catalytic quantity oftoluenep-sulphonic acid monohydrate at room temperature or by using amixture comprising acetic anhydride and a catalytic quantity oftolnene-p-sulphonic acid monohydrate.

It is unequivocally established by prior art that 160:,17a-epoxypregnan-20-ones (VI) react with hydrogen halides to forml7a-hydroxy-l6j3-halopregnan-20-ones (VII) which derivatives, ontreatment with a catalytic reducing agent, yield the corresponding17a-hydroxypregnan-ZO-ones (VIII).

We therefore concluded that the reactions had proceeded according to theexpectation of prior art and formulated our products accordingly.

Subsequently, however, we examined the reaction of the epoxide (V) withsulphuric acid in dioxan, hoping thereby to obtain the corresponding16-methyl-16,17- diol (X).

COMB

COMe

0 OMe (XII) To our surprise the product proved to be identical with thenew compound previously formulated as 17 a-hydroxy-6a,16-dimethylpregn-4-ene-3,20-dione (IX; R=H) and obtained from theepoxide (V) by successive treatment with a hydrogen halide and Raneynickel. This remark-.

droxy-6a methyl-16 methylenepregn 4-ene-3,20-dione (I; R=H, cf. XI) oras the isomer (XII). Foumulation (XI) is preferred on theoreticalgrounds. Its formulation as a conventional D-homo-structure formed fromeither (X), (XI) or (XII) by molecular rearrangement isregarded asunlikely as reduction of the carbonyl group attached to Ring D, followedby oxidation of the resulting M. i a

, (XIII) Enforced acetylation of the new compound now believed to be17a-hydroxy-6wmethyl46-methylenepregn- 4-ene-3,20-dione (I; R=H, cf. XI)yields an acetyl derivative which is a potent orally-activeprogestational agent. The formulation of the acetyl derivative as17aacetoxy-6a,lG-dimethylpregn 4 ene 3,20 dione (IX; R=Ac), must nowclearly be revised in the light of the new formulation (I; R=H) for itsimmediate hydroxylated precursor. Unfortunately, the evidence availableat the present time does not permit the conclusion to be drawn thatacylation of (I; R H) necessarily occurs to yield (I; R=Acyl) withoutconcomitant molecular rearrangement. The reason for this doubt is below.

Examination of the acetylated material by the method of nuclear magneticresonance reveals, inter alia, absorption of 4.6 parts/million relativeto tetramethylsilane as internal standard in theolefinic proton regionwhich absorption is believed to indicate (i) The presence in theacylated material of 3 ordinary inactivated protons, preferably attachedto cyclohexanic rings, and

(ii) The absence of methylene C=CH which normally shows absorption at5.2-5.4 parts/ million relative to tetramethylsilane as internalstandard. In addition, the N.M.R. absorption spectrum appears toindicate the presence of only one Me group (at C in the molecule (otherthan the angular methyl groups at C and C These observations aredifiicult to reconcile with structure (I; R=Ac) for theacetyl-derivative.

It is true that the science and art of nuclear magnetic resonance arestill in their infancy, so that conclusions reached on the basis thereofmust be accepted with caution. We nevertheless believe that the evidencepresented by the N.M.R. determinations does not permit the facileconclusion that the acyl derivatives which form the ultimate products ofthis invention are represented as simple acyl derivatives (I; R=Acy1) ofthe hydroxyl-ated precursor (I; R=H). Formulation (H; R=Acyl) isaccordingly preferred for these valuable new compounds.

Following is a description by way of example of methods of carrying theinvention into effect.

Example 1 (a) 601,16 dimethylpregna 4,16 diene 3,20-dine.-3fl-hydroxy-6,16-dimethylpregna-5,16-dien-20-one (1 g.) was dissolved incyclohexanone (24 ml.) and distilled slowly until 6 ml. of distillatehad been collected. Aluminium tert.-butoxide (1 g.) in dry toluene (16ml.) was added an the reaction mixture heated under reflux for 45minutes. Rochelle salt solution was then added and the mixture was steamdistilled for 4 hours. The steroid was extracted with ether and theether extracts were washed with water and dried. After removal of theether the residue was crystallised from methanol to give 60:,16-dimethy1pregna-4,16-diene-3,20-dione needles, M.P. 188 to 190 C.,

A523? 242 to 244 m e=23,322, [or] +65 (c., 0.338 in chloroform).

(b) 611,16 dimethyl 16,17 epoxypregn 4 ene-3,20-dione.6u,16-dimethylpregna 4,16 diene-3,20 dione g.) was dissolved inethanol (50 ml.) containing sodium hydroxide solution (40%) (2.5 ml.)apd 30% hydrogen peroxide solution ml.) was added dropwise Whilstheating the mixture under reflux. The reaction was kept at the refluxtemperature for a further 20 minutes, and then cooled; the product,which crystallised out, was filtered off and recrystallised frommethanol to yield 6ot,16-dimethyl-16,17 epoxypregn 4 ene-3,20-dione,needles, M.P. 175 to 177 C.

(c) 17a-hydr0xy-6a-methyl 16 m'ethylenepregn 4- ene-3,20dione (I;R=H).The above 16,17-epoxide (4 g.) was dissolved in glacial acetic acid(250 ml.) and benzene ml.) and treated at 0 C. with hydrogen bromide inacetic acid (50% w./v.) (6 ml.). The mixture was stirred for 30 minutesand then poured into water and the product isolated with chloroform. Theresidue from the extracts, was dissolved in acetone (250 ml.) andstirred for 4 hours with Raney nickel (10 gm.) at room temperature. TheRaney nickel was filtered 011 and the acetone was evaporated underreduced pressure. The residue was crystallised from acetone/ hexane togive l7oc-hYdI'OXY 6a methyl 16 methylenepregn-4-ene- 3,20-dioneneedles, M.P. 210 to 212 C. M1 15 (c., 0.598 in chloroform),

#332? 239.5 mp, e=17,638; ,21%

1708, 3485, 3605 Gin- (d) Acetyl derivative derived from hydroxy6amethyl 16 methylenepregn 4 ene 3,20 dione (II;R=Ac).-17a-hydroxy-6u-methyl 16 methylenepregn- 4-ene-3,20-dione (I;R=I-I) (1 g.) and p-toluene sulphonic acid monohydrate (500 g.) weredissolved in glacial acetic acid (40 ml.) and acetic anhydride (8 ml.)and the mixture was left at room temperature for 8 hours. Water wasadded to the reaction mixture and after standing overnight the productwas extracted with ether. The ether extracts were washed with water,sodium bicarbonate solution, water, dried and evaporated under reducedpressure. The residue was crystallised from acetone/hexane to give theacetyl derivative derived from 17m-hydroxy- 6a-methyl-16-methylenepregn4 ene-3,20-dione characterised by rig? 239 mu, 10g 6 1.19; 3 59 1738,1715, 1666 and 1615 om.

Example 2 Acetyl derivative derived from l7a-hydroxy-6a-methyl-16-methylenepregn-4-ene-3,20-di0ne (II;R=Ac).17ahydroxy-6a-methyl-16-methylenepregn-4-ene-3,20 dione (I; R=H)(1 g.) and p-toluene sulphonic acid monohydrate (3-00 mg.) were stirredat room temperature in acetic anhydride (20 ml.) for 18 hours. Thesuspension was poured into water and the excess anhydride allowed tohydrolyse. The precipitate was filtered off, washed and dried. It wasdissolved in methanol (100 ml.) and treated with potassium hydroxide(0.9 g.) dissolved in water (4 ml.) and methanol (10 ml.) for 7 minutesat room temperature. Acetic acid (2 ml.) was added and the solutionevaporated under reduced pressure to a small volume. Water was added andthe precipitate was collected and dried. The product was purified bychromatography on an alumina column, when the benzene eluates gave theacetyl derivative derived from 17a-hydroxy-6a-methyl- 16-methylenepregn4 ene 3,2-0 dione crystallising in needles from aqueous methanol, M.P.203 to 207 C., [(1113 -99 (c., 0.214 in chloroform),

253. 0 a g 6 4.19) Example 3 Caproyl derivative derived from17a-hydr0xy-6a-methyl 16 methylenepregn 4 ene 3,20 dione (II; R: CO.C H.17u-hydroxy-6a-rnethyl-16-methylenepregn- 4-ene-3,20-dione (1.0 g.) wastreated with n-caproic anhydride (22 m1.) and toluene-p-sulphonic acidmonohydrate (0.5 g.) for 20 hours at 45 C. Aqueous pyridine was addedand the mixture was steam-distilled for 1 hour and the product isolatedwith ether to give the caproyl Lactose, B.P 125 g.

Magnesium stearate A sufficient quantity.

Starch paste, 10% A sufiicient quantity.

Starch, B.P Sufficient to produce Prcess.--The steroid, lactose, andtwo-thirds of the starch were mixed together, moistened with a suitablequantity of starch paste and granulated through a No. 20 mesh screen.

The granule was dried at 50 0., again passed through a No. 20 meshscreen, and the magnesium stearate added, together with sufficientstarch to produce the required weight. The granule was compressed toproduce tablets each weighing 150 mg.

We claim:

1. A process for the preparation of17a-hydroxy-6amethyl-16-methylenepregn-4-ene-3,20-dioue which comprisesoxidising 3 8-hydroxy 6,16 dimethylpregna 5,16- dien-ZO-one by theOppenauer procedure to give 6a,l6-dimethylpre'gna-4,16-diene-3,20-dione, reacting the 60;,16-dimethylpregna-4,l6-diene-3,20-dione with alkaline hydrogen peroxide togive a 16,17-epoxide, treating the epoxide with a hydrogen halidefollowed by treatment with Raney nickel in an organic solvent.

2. A process as claimed in claim 1 wherein the 6a,l6-dimethylpregna-4,l6-diene-3,20-dione is reacted with the alkalinehydrogen peroxide in a water-miscible organic solvent at temperaturesbetween 0 C. and 100 C.

3. A process as claimed in claim 1 wherein the epoxide is treated withhydrogen bromide in an aliphatic acid and an inert solvent.

4. A process as claimed in claim 1 wherein the epoxide: is treated withaqueous hydrogen iodide in a water-.

miscible organic solvent.

5. A process as claimed in claim 1 wherein the reaction with Raneynickel is performed in ethanol.

6. A process wherein the 17oz-hydroxy-6a-methyl-l6-methylenepregn-4-ene-3,20-dione prepared as claimed in claim 1 isacylated.

7. 17a-hydroxy-6a-methy1-1G-methylenepregn 4 ene- 3,20-dione.

8. Acyl derivatives wherein the acyl groups have up to 10 carbon atomsderived from 17oc-hydroxy-6a-methyl- 16 methylenepregn-4-ene-3,20-dione.

9. 6a,l6-dimethyl-l6,17-epoxypregn-4-ene-3,20-dione. 10.l7a-acetoxy-6a-methyl-l6-methylenepregn-4 ene- 3,20-dione.

11. l7m-caproyloxy-6a-methyl-lG-methylenepregn 4- with alkaline hydrogenperoxide to give a 16u,17a-8POXld6;

oxidizing the 3B-hydroxy group by Oppenauer procedure to give the3-keto-A structure, and cleaving the l6u,l7aepoxide with hydrogenbromide.

References Cited by the Examiner UNITED STATES PATENTS 2,787,623 4/1957Gebert 260397.4' 2,871,246 l/l959 Loken 260397.4 2,878,247 3/1959Miramontes et al. 260239.55

LEWIS GOTTS, Primary Examiner.

L. H. GASTON, JULIUS FROME, Examiners. M. LIEBMAN, E. ROBERTS, AssistantExaminers.

9. 6A,16-DIMETHYL-16,17-EPOXYPREGN-4-ENE-3,20-DIONE.